This project is designed to (a) elucidate human genes which are important in the control of gene expression and to (b) determine gene linkage relationships of these and other gene markers. These aspects of human development will be studied in a parasexual genetic way employing man-mouse somatic cell hybrids. Many of these studies involve the genetic characterization of a group of acid hydrolases associated with lysosomes. Genes important in the final expression of lysosomal hydrolases will be studied employing normal and enzyme deficient human fibroblasts in hybrid combinations with mouse cells. Several of the enzymes are associated with such neurodegenerative diseases as Tay Sachs disease, Sandhoff-Jatzkewitz disease, metachromatic leukodystrophy and generalized gangliosidosis. These studies are designed to provide a better understanding of the genetics of lysosomal enzymes and their deficiencies and hopefully, to aid in the prenatal diagnosis of lysosomal storage diseases. It is hoped that such information will help to construct models of lysosomal biogenesis and regulation. Proliferating man-mouse somatic cell hybrids are particularly suited for this study since human chromosomes, but not mouse chromosomes are lost which provides the mechanism to identify human genes and linkage relationships if human and mouse gene markers can be distinguished. The mapping of human genes to linkage groups requires a large number of markers. It is planned to increase our present catalogue from about 30 human enzyme markers to 50 markers by optimizing procedures for new enzymes, ribosomal proteins and membrane proteins. These data will increase the chances of placing a biochemical marker on each human chromosome.